Oxandrin

ABSTRACT. Background: The aim of this study was to measure changes in body cell mass (BCM) and quality of life in HIV-infected individuals undergoing oxandrolone therapy. Previous studies on oxandrolone have neither quantified changes in BCM using criterion methods nor quality of life using an HIV-specific instrument. Methods: Twenty-five HIVinfected patients (15 with an AIDS diagnosis) on standard antiretroviral and nutrition management were studied before and an average of 18.6 weeks after the initiation of oxandrolone therapy, as prescribed by their primary care physician for the treatment of weight loss. BCM was estimated from intracellular water measured by multiple dilution. Lean soft tissue mass (LTM) was measured by dualenergy X-ray absorptiometry. Quality of life was evaluated by the Functional Assessment of HIV Infection (FAHI) ques

tionnaire. Results: Significant gains in body weight (2.6 +/- 3.0 kg; p

Although clinically definable AIDS wasting syndrome has decreased with the advent of protease inhibitors and highly active antiretroviral therapy (HAART), HIV-infected individuals may still experience a disproportionate loss of lean tissue with or without weight loss, both of which have been associated with poor clinical outcome.1,2 The lipodystrophy that many HIV-infected individuals on protease inhibitor therapy experience remains to be elucidated in terms of its contribution to morbidity and potential masking of lean tissue wasting in this population.3 Nevertheless, loss of lean tissue, and body cell mass (BCM) in particular, remains a vital concern because it frequently precedes overt weight loss and can independently predict mortality in HIV infection. 1,2,4-7 In addition, weight loss and wasting have been reported to adversely impact perceived well-being and quality of life in HIV-infected individuals.8-14 It has yet to be established whether or not reversal of weight loss or repletion of BCM can significantly improve quality of life.

Intervention strategies for weight loss and wasting in HIV infection have taken many approaches. Nutritional supplementation/support and appetite stimulants have been shown to promote weight gain; however, in the studies in which body composition was assessed, these strategies have been shown to result primarily in fat, rather than lean tissue, gains. 15-27 Short-term progressive resistance exercise has been shown to lead to lean tissue gains.2,28 The use of anabolic agents such as growth hormone, testosterone, and injectable testosterone derivatives with or without resistance exercise have been successful in repleting lean tissue; however, each has some drawbacks.28-40 Growth hormone is costly, and testosterone and testosterone derivatives such as nandrolone decanoate can cause adverse side effects such as masculinization in women, liver abnormalities, and acne.2

Oxandrolone is an orally administered testosterone derivative with a favorable anabolic:androgen ratio and safety profile that has been demonstrated to promote weight and lean tissue gains with a minimization of adverse side effects in HIV-infected individuals.1,38,41-46 However, there is a deficit in the existing literature on oxandrolone in terms of its ability to impact the specific subcomponent of the lean tissue compartment most related to nutritional status, the BCM.

It is well recognized that BCM is a valuable clinical outcome parameter and an ideal standard by which to assess nutritional status, because its assessment provides a measure of total body protein and metabolically active, functional tissue. 47-49 Although there are several criterion or "gold standard" methods available to estimate BCM indirectly, including total body potassium counting, neutron activation analysis, and the multiple dilution method, they have not been used in clinical studies of oxandrolone, which may be at least partly because of the limited availability and high cost of these methods. In addition, there has been a notable paucity of field methods to provide valid measures of BCM in the clinical setting. We have recently reported data supporting the validity of bioimpedance spectroscopy (BIS) to measure BCM changes in HIV infection. 50 Previous studies on oxandrolone have measured lean tissue changes using methods such as dual-energy X-ray absorptiometry (DXA) or single-frequency bioelectrical impedance analysis (BIA), neither of which can be considered valid for measuring the BCM compartment in HIV infection.

The primary aim of this study was to document changes in BCM using a valid criterion method (multiple dilution) and perceived quality of life using a comprehensive HIV-specific questionnaire in HIV-infected individuals undergoing 4 months of oxandrolone therapy.

MATERIALS AND METHODS

Study Description

This was a prospective descriptive study of HIVinfected individuals who were undergoing treatment for weight loss with the anabolic corticosteroid, oxandrolone (Oxandrin; BTG Pharmaceuticals, Iselin, NJ). At the time of study initiation (September 1997), oxandrolone was relatively new on the list of treatment options for weight loss in HIV infection. Given that its safety and efficacy had been previously demonstrated,41 it was our aim to provide a description of changes that occurred after oxandrolone was added to the standard antiretroviral regimen that individuals were receiving. In addition, standard care for individuals with a history of weight loss in the clinic from which subjects were recruited included nutrition assessment and monitoring by a registered dietitian; thus, all study participants were assessed and monitored to optimize nutritional status throughout the study. Subjects were requested to maintain their usual physical activity routine throughout the study.

Twenty-five patients were enrolled over a 2-year period (1997 to 1999). Once an individual and his or her physician decided to initiate oxandrolone therapy, the individual was recruited to participate in the study, all procedures were explained, and written consent was obtained. Baseline testing was scheduled within the following 1 to 2 weeks to avoid delay of oxandrolone initiation. Body water [total (TBW), intracellular (ICW), and extracellular (ECW)], BCM, bonefree lean soft tissue mass (LTM), bone mineral mass, resting energy expenditure (REE), dietary intake, and quality of life parameters were assessed at 2 time points: before initiating oxandrolone (baseline) and after approximately 4 months of oxandrolone therapy (study conclusion). Time on study averaged 18.6 weeks; only 4 subjects deviated markedly from this mean, with final measurements at 6, 28, 35, or 40 weeks.

Human Subjects

Subjects were recruited from an outpatient clinic with a population of approximately 600 HIV-infected patients. All individuals over age 18 years with a history of weight loss (5% or more from premorbid weight), who were receiving standard antiretroviral therapy and whose primary care physician prescribed oxandrolone therapy, were recruited to participate in this study. Males with prostate cancer, pregnant or lactating females, and anyone with renal disease, hepatic disease, severe dementia, history of medication noncompliance, or those with poor functional status were excluded from the study. Thirty-one subjects underwent baseline assessment, after which 6 individuals dropped from the study, constituting a 19% attrition rate. Reasons for attrition included the following: relocation (2 subjects); loss of interest in participating (2 subjects); and 2 reports of adverse side effects (acne and elevated liver function tests), both occurring within 2 to 3 weeks of the initiation of oxandrolone therapy.

Twenty-five subjects (24 male, 1 female) between thE ages of 27 and 56 years (mean age, 40.9+/-7.2 years; completed the study. The ethnic composition of thE subject population was 16 white, 6 Hispanic, and African American. Of these, 24 subjects (23 male, I female) were maintained on an oxandrolone dose of 2( mg/d, while 1 subject's daily dose was reduced to 10 mg after 4 weeks. One of the subjects experienced elevated liver function tests that resulted in early cessation of oxandrolone after 6 weeks. The study subjects hat been HIV positive for an average of 7.2 4.2 years before study entry. Fifteen subjects had an AIDS diag. nosis, and 12 subjects had lost at least 10% of them usual body weight in the 6 to 12 months before thE start of the study. All 25 subjects were on combination antiretroviral therapy, and 19 of the subjects werE taking protease inhibitors. Ten subjects had an activE opportunistic infection at the time of study entry including infection with cryptosporidium, herpes virus or papilloma virus; thrush; toxoplasmosis; or pneumoo cystis carnii pneumonia. In all but 3 subjects, opportu nistic infections were resolved by the time of studs conclusion. No new opportunistic infections developer in any subject over the course of the study. Although CD4+ count and viral load was not measured specifi tally for the study, information regarding CD4+ count and viral load was available for 23 subjects at the timE of study entry. CD4+ counts ranged from 44 to 78( cells/mm3, with a mean of 319 +/- 186 cells/mm 3. Twelve subjects had a viral load

Anthropometric Assessment

Body weight (Wt) was measured to the nearest 0.05 kg with a digital platform scale (Kubota model K-10300L-A; Chugai Boyeki (America) Corp, Commack, NY). Subjects were instructed to wear the same lightweight clothing at each visit. Standing height (Ht) was measured to the nearest 1 mm with a stadiometer (Narragansett Machine Co, Providence, RI).

Body Water Volumes Determination

Criterion estimates of TBW and ECW were derived from deuterium (^sup 2^H) and bromide dilution, respectively: While still in a fasted state, and after baseline urine and venous blood samples were collected, subjects were given a weighed dose of deuterium oxide (^sup 2^H^sub 2^O; 99.8 atom%; Isotec Inc, Miamisburg, OH) equivalent to 0.15 g/kg TBW. To calculate the dose, an estimate of TBW was obtained by single-frequency bioelectrical impedance analysis.51 Immediately afterward, the subjects drank a measured dose of a sodium bromide (NaBr; Sigma, St. Louis, MO) solution, providing 1.0 mL of 3% (wt/vol) solution per kilogram of body weight. A 3-hour equilibration period, during which subjects did not ingest anything, was allowed for ECW determination by bromide dilution. A second blood sample was drawn at 3 hours postbromide dosing, and a light snack was provided immediately after the second blood draw. At 5 and 6 hours after dosing with ^sup 2^H^sub 2^O, urine samples were collected for TBW determination by 2H dilution. Urine samples were analyzed for ^sup 2^H enrichment by isotope ratio mass spectrometry.52 TBW was calculated as described by Schoeller et al. Serum bromide enrichment was determined by highperformance liquid chromatography (HPLC).54 ICW was estimated as the difference between TBW and ECW.

BCM Determination

BCM was estimated from ICW measured by dilution (liters TBW by deuterium dilution - liters ECW by bromide dilution = liters ICW x 0.9937 = kg ICW), using the following equation: kg BCM = kg ICW/0.70. This is based on the assumption that cells are comprised of 70% water.47

LTM Determination

DXA measurements of the total body were made and analyzed by a Lunar (model DPX-L; Lunar Radiation Corp, Madison, WI) total body scanner and software version 1.3 using the extended research analysis mode to determine bone-free LTM, bone mineral content, total fat mass, and truncal fat mass. All scans were performed and analyzed by the same technician, using the calibration and measurement procedures recommended by the manufacturer.

REE Determination

REE was measured by indirect calorimetry using an open-circuit indirect calorimeter (Deltatrac MBM-100; SensorMedics, Yorba Linda, CA) while subjects were in a fasted state, and after dosing with deuterium oxide and sodium bromide. Instrument calibration was performed before each REE measurement. Standardized measurement procedures were followed.55 REE was derived using the Weir equation: REE = [3.941 (Vo2) + 1.106 (VCO^sub 2^)11.44 - 2.17 (TUN); where REE = resting energy expenditure (kilocalories per day), VO^sub 2^ = oxygen consumption (milliliters per minute), VC^Sub 2^ = carbon dioxide production (milliliters per minute), and TUN = total urinary nitrogen (grams per day).56 Subjects collected urine over a 24-hour period for TUN quantification twice during the study, during the weeks before baseline and study conclusion.

Nutritional Assessment

Each subject underwent a complete nutrition assessment at the time of baseline measurements. A nutritional history was taken, including detailed information regarding current and previous use of vitamin and mineral supplements, calorie or protein supplements, and an investigation into the current or recent presence of clinical symptoms that might interfere with food intake or absorption. A weight history was taken through review of the medical record and patient interview. Current weight was evaluated by comparison to premorbid weight and weight taken 1 to 6 months before date of assessment, if available. Medications were noted and reviewed for drug-nutrient interactions and nutritional implications. Follow-up nutritional care was provided on a monthly basis to evaluate the efficacy of previous nutritional care plans, to identify any new nutritional problems, and to assist the subject with any symptoms that could be interfering with intake or absorption. Liquid nutritional supplements (depending on taste preference and donated sample availability: Ensure and Ensure Plus; Ross Products Division, Abbott Laboratories, Columbus, OH and Boost and Sustacal; Mead Johnson, Evansville, IN) or protein powder (Optimune; Optim Nutrition, Salt Lake City, UT) were provided by the clinic as needed to individuals who reported difficulties maintaining an adequate kilocalorie or protein intake; "adequate" was defined as estimated intake meeting at least 90% of assessed requirements (energy: 5.02 to 5.86 x kJ/d REE and protein: 1.3 to 1.5 g/kg body weight).

Dietary Intake Evaluation

Nutrient intake was assessed by dietary records kept on 3 nonconsecutive assigned days during the week before each testing visit. Of primary interest was the dietary protein and kilocalorie content. Before baseline measurement, subjects were instructed on how to keep the dietary records, including detailed instructions on how to estimate the amount of foods and liquids consumed. Subjects were encouraged to use measuring spoons and cups whenever possible. Dietary records were reviewed at each testing visit and analyzed later for nutrient content using the Minnesota Nutrient Data System in collaboration with the Nutritional Assessment Laboratory at The University of Arizona.

Quality of Life and Appetite Assessment

Quality of life was assessed by the self-administered Functional Assessment of Human Immunodeficiency Virus Infection (FAHI) quality of life instrument.57 The FAHI includes a comprehensive battery of items, including subscales assessing physical, social, emotional, and functional status, that can stand alone as subscales for specific domains and can be included in an overall score for global assessment. Written consent to use the FAHI was obtained from the author before the initiation of the study. The latest version (version 3) of the FAHI instrument available at study initiation was used. The instrument contained 37 individual items that were scored. Subscale scores were obtained for the following domains within the FAHI: physical well-being (7 items); social/family well-being (7 items); relationship with doctor (2 items); emotional well-being (5 items); functional well-being (7 items); and HIVspecific additional concerns (9 items). Subjects were asked to rate on a 5-point response scale how true a series of statements were for them during the previous 7 days. Responses were as follows: 0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; and 4 = very much. Items within each subscale were reverse coded, as appropriate, based on scoring guidelines provided by Cella et al.57 Missing items were handled by prorating the subscale score using the following equation: prorated subscale score = (sum of item scores) x (number of items in subscale)/(number of items answered). According to the guidelines, >50% of the items in a subscale had to be answered to maintain the validity of the subscale after prorating the score. A score was obtained for each of the 6 subscales within the FAHI and were then summed to get an overall FAHI quality of life score. Appetite was assessed at each testing visit by the Functional Assessment of Anorexia/Cachexia Therapy (FAACT), which addresses HIV-specific concerns affecting appetite and food intake.57

Data Analysis

Statistical analyses were obtained using the SPSS for Windows, version 10.0 software (SPSS Inc, Chicago, IL). Paired t tests were used to analyze differences in body weight, body composition, dietary intake, and quality of life parameters from baseline to study conclusion. Independent t tests were used to compare changes in parameters between individuals with an AIDS diagnosis (AIDS; n = 15) with those who had not yet progressed to AIDS (HIV+; n = 10). The Pearson's product moment correlation (r) was used to evaluate the relationship between changes in BCM or weight and change in overall quality of life, reflected by change in total FAI score. Correlational analyses were also used to evaluate the association between changes in BCM or body weight and functional status, physical well-being, and appetite scores. The FAACT appetite scale and each FAHI subscale were analyzed for internal reliability by Cronbach's ot.

RESULTS

A comparison of subject characteristics at baseline and study conclusion are presented in Table I. Overall, individuals receiving oxandrolone therapy in conjunction with standard antiretroviral and nutrition management exhibited a significant increase in body weight, TBW, ICW, BCM, LTM, and REE after a mean of 18.6 weeks of treatment. ECW, bone mineral content, and total and truncal fat mass did not change over the course of the study. Body weight increased by an average of 2.6 +/-3.0 kg, BCM increased by an average of 3.7 +/-3.0 kg, and LTM increased by an average of 3.0 +/- 2.9 kg. One subject did not complete baseline evaluation by DXA; thus, only 24 subjects could be included in the determination of LTM, bone, and fat mass change over the study. The change in BCM measured by multiple dilution and the change in LTM measured by DXA were not different (p = .334). As expected, the increase in BCM was correlated with an increase in REE (r = .52, p = .008). Changes in body weight and composition parameters were not different between the individuals with AIDS and those who were HIV+, with the exception of change in total and truncal adiposity. The HIV+ individuals exhibited a significant decrease in both total fat mass (-1.7 +/-2.4 kg; p = .05) and truncal fat mass (-1.1 +/- 1.3 kg; p = .03) from baseline to study conclusion. Total and truncal fat mass did not change in the AIDS group. Baseline and study conclusion dietary intake data were available for 22 subjects, and on average, no change in energy or protein intake occurred over the course of the study. No differences were noted in dietary intake parameters between the HIV+ and AIDS subgroups.

The changes in select quality of life parameters from baseline to study conclusion are shown in Figure 1. Appetite improved (p = .032), and overall quality of life improved with trend level significance (p = .056) over the course of the study. Weight gain was significantly associated with an increase in overall quality of life (p = .040; Fig. 2) and appetite (p = .022; Fig. 3). Weight gain was also correlated with improved physical wellbeing, with trend level significance (p = .054). Changes in quality of life parameters did not differ between individuals who were HIV+ and those with AIDS. Reliability analysis revealed that the 7-item physical wellbeing subscale of the FAHI had excellent reliability, with a Cronbach's ot of 0.91 (n = 23). The 7-item functional status subscale had adequate reliability, with a Cronbach's a of 0.78 (n = 23). The 18-item appetite scale (FAACT) also had adequate reliability, with a Cronbach's a of 0.77 (n = 23).

DISCUSSION

The most important findings from this study are that HIV-infected individuals receiving oxandrolone therapy in conjunction with standard antiretroviral and nutrition management over a 4-month period were observed to gain both body weight and BCM and to experience improved appetite and quality of life. It is also important to note that the oxandrolone treatment seemed to be well-tolerated by the patients. Of the 25 individuals who completed the study, only 1 experienced a significant adverse event, in the form of elevated liver function tests, that caused him to stop taking the oxandrolone. The subject whose dose was reduced from 20 to 10 mg/d after 1 month reported an unexplained feeling of anxiety that he attributed to the oxandrolone. Our findings are consistent with previous reports on the relative safety and efficacy of oxandrolone to promote weight and lean tissue gains in HIV-infected individuals.38,41-45 Our study is unique among other studies of oxandrolone in that we have conducted a more comprehensive evaluation of both body composition and quality of life changes over a course of treatment.

The substantial gain in BCM that occurred is compelling, given that BCM is the target tissue of interventions aimed at improving nutritional status. Three other findings provide supportive evidence for the observed repletion of BCM. First, the fact that TBW measured by deuterium dilution increased significantly, and ECW by bromide dilution did not change, reinforces the fact that there was a significant increase in ICW. This is important, given that anabolic corticosteroids can induce changes in fluid status with expansion of ECW. Given the relationship between ICW and BCM, the fact that ICW increased implies a concurrent increase in BCM. Because the dilution method is widely accepted as a gold standard for measuring ICW and BCM in any population, the observed increase in BCM can be considered valid in this population of HIV-infected individuals. Second, DXA also detected a significant change in LTM, which is the more global lean tissue compartment that contains the BCM. The fact that there was no difference between the change in BCM measured by multiple dilution and the change in LTM measured by DXA reinforces the notion that a change occurred in the target tissue, ie, BCM, in these subjects. Third, REE measured by indirect calorimetry increased significantly over the treatment period and was strongly correlated with BCM change. Given that BCM is the metabolically active, oxygen-consuming, energy-burning tissue of the human body, we expected that an increase in BCM would be accompanied by a corresponding increase in REE. This was indeed the case in the current study. These findings reinforce the importance of BCM as a clinical parameter for nutritional status and confirm it as a marker for gauging the effectiveness of intervention strategies for weight loss.

This was the first study of individuals receiving oxandrolone that measured BCM using criterion methods. All previous studies that reported the effects of oxandrolone on BCM used single-frequency BIA or DXA to measure lean tissue changes, neither of which can be considered truly valid for measuring BCM in HIV infection. These methods are based on the assumptions of a two-component body composition model that may be violated in the disease state. We have recently reported data supporting the validity of BIS and demonstrating the inability of single-frequency BIA field techniques to accurately estimate BCM change in this population.so

Despite the differences in methods used to measure changes in lean tissue, it is interesting to compare the findings from this study to other published reports on oxandrolone. The average gain in BCM experienced by the subjects in this study (3.7 +/- 3.0 kg) was higher than the 2.2-kg average BCM gain reported for 21 individuals on oxandrolone after 4 months,43 and was comparable with the nonsignificant average BCM gain of 3.0 kg reported for 21 patients receiving 120 days of oxandrolone therapy.45 In addition, the average gain in body weight by subjects in this study was 2.6 +/- 3.0 kg, compared with an average of 4.3 kg reported in clinically stable individuals with minimal weight loss,43 an average of 1.8 kg in individuals with AIDS Wasting Syndrome,41 and a nonsignificant average of 7.3 kg in individuals with minimal weight loss.41 More recently, gains in LTM by DXA of 6.9 +/-1.7 kg were reported in HIV-infected individuals undergoing treatment with progressive resistance training and 20 mg/d oxandrolone.38 There seems to be a significant advantage to a combined approach of progressive resistance training with oxandrolone. Nevertheless, the repletion of BCM observed in our study participants after oxandrolone therapy in the absence of progressive resistance training is impressive.

The lipodystrophy that has been observed in individuals receiving protease inhibitor therapy has been and continues to be an enigma. Investigators have suggested that anabolic agents may potentially attenuate or even reverse this process; in fact, it has been observed that in non-HIV-infected obese men, abdominal fat was reduced after oxandrolone therapy.58 We observed that HIV-infected individuals who had not yet progressed in their disease to AIDS (the majority of whom were receiving protease inhibitor therapy) responded positively to oxandrolone therapy by exhibiting a significant reduction in truncal fat measured by DXA. It is difficult to say why this reduction was observed in these individuals but not in those who were farther advanced in their disease. Given that there were an equal number of individuals within each group who had exhibited a significant degree of wasting, and the fact that opportunistic infections were essentially stable throughout the duration of the study, the answer to this question is not readily apparent.

It is interesting to note that dietary intake did not change, although appetite was reported to increase over the course of the study. This was somewhat surprising, given that the subjects underwent comprehensive nutrition assessment with ongoing nutritional monitoring throughout the study, and that body weight significantly increased over the study. This observation could be interpreted in several ways. First, this discrepancy might be attributed to errors associated with dietary recording. There are no reported data available regarding the reporting patterns of HIV patients, ie, whether they tend to under- or overreport dietary intake. It could be that individuals in this study, having undergone comprehensive nutrition counseling on the importance of consuming an adequate intake to manage weight loss, might have overreported dietary intake at the initial assessment (baseline) to appear cooperative with the outlined goals of the study. It is also possible that as dietary records were reviewed by the Registered Dietitian and subjects were corrected for recording technique, subjects learned how to more accurately estimate portions consumed. Thus, subjects could have improved their recording technique over the course of the study, so that the overestimation errors may have been minimized at study conclusion. This could explain why we did not detect a change in dietary intake.

It might also be surmised that nutrition management by the registered dietitian led to a maintenance of dietary intake over the course of the study. Part of the nutrition management process involved the provision of liquid nutritional supplements alone, or in combination, with a protein supplement (Optimune; Optim Nutrition) as deemed appropriate by the registered dietitian working with the subjects. Dietary records indicated that the majority of individuals participating in the study did take nutritional supplements throughout the duration of the study. One plausible explanation for the fact that energy and protein did not change significantly after treatment may be that subjects decreased intake of regular foods to compensate for the increase in energy or protein provided by supplements.

Another unique aspect to this study was the use of an HIV-specific quality of life assessment tool (FAHI). Although the concept of evaluating the impact of any clinical intervention on health-related quality of life has been gaining recognition as an important addition to clinical trials, few studies of anabolic interventions for HIV patients have included comprehensive quality of life assessment in their protocols. This may be because of the fact that, although there are many different health-related quality of life instruments, there has not been a consensus on the best way to assess quality of life.14,59 Furthermore, there have been few instruments available that address the specific issues relating to HIV infection. The FAHI is one of the few available questionnaires that addresses both general and HIV-specific quality of life concerns.

It is encouraging that perceived quality of life and appetite improved over the course of the study. However, given the clinical importance of BCM change, it is somewhat surprising that weight gain, but not BCM gain, was associated with improvement in perceived quality of life in this population of HIV-infected individuals with a history of weight loss. In particular, based on other reports of a significant relationship between lean body mass and perceptions of physical function in HIV-infected men,6 it seemed reasonable to expect a relationship between change in BCM and perceived physical well-being and functional status, even if there was no association with overall quality of life. However, this was not the case in our study.

These results are not entirely inconsistent with previous research. For example, individuals who gain weight after treatment with megestrol acetate report a significant improvement in perceived well-being and appetite, even when the majority of the weight gained is body fat.21-22 It may be that weight gain is a more directly perceivable physical change than an increase in BCM. Individuals who regain lost weight may be more likely to notice an improvement in their outward appearance, associated with a positive gain in perceived well-being and other quality of life parameters, than individuals who merely experience an increase in BCM with weight gain of a lesser magnitude.

There were a few limitations to the current study. First, because the current study was not a randomized, placebo-controlled study, causal relationships could not be determined. For example, it is impossible to say for certain which aspect of the combined therapeutic approach applied to our subjects was most responsible for the observed increases in BCM and body weight. Given that previous controlled studies have established the efficacy of oxandrolone therapy for treatment of weight loss in HIV-infected individuals and other clinical populations, it can be argued that it is no longer ethically sound to pursue additional placebocontrolled studies of oxandrolone. Indeed, in the clinical setting from which our subjects were recruited, the consensus was that a more inclusive trial was preferable to a placebo-controlled one, so that oxandrolone could be more broadly applied to the patient population. To minimize this limitation in the study design, each subject served as his own control, and baseline measurements were taken in all cases before initiating oxandrolone therapy. Given that the addition of oxandrolone at baseline was the primary change to the standard combined therapeutic approach of antiretroviral therapy and ongoing nutrition management for study participants, it seems logical to suggest that the observed gain in BCM and body weight can be at least partly attributed to the initiation of oxandrolone therapy.

A second limitation involves the difficulty in obtaining an accurate assessment of dietary intake in freeliving individuals. Without confining study subjects to a metabolic ward, quantification of dietary intake is subject to recording error. Furthermore, errors in data analysis may also contribute to problems interpreting dietary intake data. Although substantial efforts were made to minimize the error associated with analyzing dietary intake data collected in this study, it is possible that these problems could have contributed to the failure to detect significant changes in relation to dietary intake. Unfortunately, these issues are difficult to resolve. The assessment of dietary intake has been the focus of much research interest and is likely to remain an issue in clinical trials in free-living subjects.61,62

With continuing improvement in clinical management strategies for HIV infection, there has been a critical shift in the management of HIV infection as a chronic rather than terminal disease. This shift has led researchers to focus on the improvement of supportive therapies. Despite these improvements, weight loss and pathologic changes in body composition remain a critical issue for HIV-infected individuals. Although outcome parameters in clinical trials have been expanded beyond life and death, the focus of most research has been on clinical indicators, such as CD4+ count, viral load, BCM repletion, or weight gain. Although these are all important outcome parameters for gauging improvement in clinical and nutritional status, it is increasingly important to consider both physical and psychological well-being in response to clinical interventions. We aimed to evaluate changes in both domains in this study.

The results of this study provide support for the use of oxandrolone to treat weight loss in HIV infection, given that a significant change in BCM, body weight, appetite, and quality of life occurred in individuals receiving oxandrolone therapy in conjunction with standard antiretroviral and nutrition management. The findings from this research also underscore the importance of using valid methods to document BCM changes in response to an intervention strategy. The importance of BCM as a clinical outcome parameter cannot be overemphasized, based on the growing body of knowledge indicating its relationship to morbidity and mortality in this and other clinical populations. Although total body potassium counting and multiple dilution continue to remain in the research domain, field techniques such as BIS have been proven to provide valid estimates of BCM in the setting of HIV infection.

Therapies such as oxandrolone hold promise as part of a combined approach to managing the weight loss and pathologic changes in body composition associated with HIV infection. In fact, some researchers have speculated on the potential efficacy of oxandrolone to counter fat redistribution in HIV-infected individuals, based on the observation that it reduces abdominal fat in obese non-HIV-infected men.58,63 Our observation of a reduction in truncal fat after oxandrolone treatment, at least in individuals in the early stages of HIV infection, would seem to support this notion. Further study on the potential effects of oxandrolone on lipodystrophy is certainly needed.

In conclusion, it is encouraging that nutritional status, in addition to quality of life, can be positively impacted in HIV-infected individuals receiving a combined therapeutic intervention strategy for weight loss.

ACKNOWLEDGMENTS

The authors thank the patients, physicians and staff at El Rio Special Immunology Associates, Tucson, AZ for their assistance with this research.

The authors thank Dr Linda Houtkooper and the Nutritional Assessment Laboratory at The University of Arizona for assistance with the analysis of nutrient intake, Drs Timothy Lohman and Scott Going in the Department of Physiology at The University of Arizona for assistance with DXA scans, and Dr Jennifer Rood at Pennington Biomedical Research Center for her input on bromide analyses. The study was supported by an American Dietetic Association Foundation Dietitians in Nutrition Support Dietetic Practice Group Research Award, a Kraft Foods Fellowship, and a Helen S. Mitchell Nutrition Scholarship; a Kappa Omicron PhiHettie Margaret Anthony Fellowship; and a BTG Pharmaceuticals, Iselin, NJ gift grant.

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Carrie P. Earthman, PhD, RD*^; Phyllis M. Reid, BS*; Ingeborg T. Harper, BS^^*; Eric Ravussin, PhD^^*; and Wanda H. Howell, PhD, RD, CNSD*

From the *Department of Nutritional Sciences, The University of Arizona, Tucson; ^Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, ^^Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona; and Pennington Biomedical Research Center, Baton Rouge, Louisiana

Received for publication, September 25, 2001.

Accepted for publication, July 10, 2002.

Correspondence: C.P. Earthman, PhD, RD, Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, VA 240610430.

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